Examples of the known process for producing sugar nucleotides include: 1) chemical syntnetic processes (Adv. carbohydr. Chem. Biochem., 28, 307 (1973), Bull. Chem. Soc. Japan, 46, 3275 (1973), J. Org. Chem., 57, 146 (1992), Carbohydr. Res., 242, 69 (1993)); 2) production processes using enzymes (J. Org. Chem., 55, 1834 (1990), J. Org. Chem., 57, 152 (1992), J. Am. Chem. Soc., 110, 7159 (1988), Japanese Published Unexamined National Publication No. 508413/95, Japanese Published National Publication No. 500248/95, WO 96/27670); 3) processes using microbial cells such as yeast and the like (Japanese Published Examined Patent Application No. 2073/70, Japanese Published Examined Patent Application No. 40756/71, Japanese Published Examined Patent Application No. 1837/72, Japanese Published Examined Patent Application No. 26703/72, Japanese Published Examined Patent Application No. 8278/74, Japanese Published Unexamined Patent Application No. 268692/90); and 4) an extraction process from microbial cells of halo-tolerant yeast (Japanese Published Unexamined Patent Application No. 23993/96).
However, the process 1) requires expensive materials (for example, morpholidate derivative of nucleoside-5′-monophosphate (referred to as “NMP” hereinafter), sugar phosphate, etc.); the process 2) requires expensive materials (for example, nucleoside-5′-diphosphate (referred to as “NDP” hereinafter), nucleoside-5′-triphosphate (referred to as “NTP” hereinafter), phosphoenolpyruvate, etc.), and various enzymes (e.g., pyruvate kinase, etc.); and the process 3) requires drying treatment of microbial cells. Including the process 4), all of the above-mentioned processes use expensive nucleotides, sugar phosphates, and the like or have a difficulty in effecting large scale production from the operational point, of view, so that an industrial scale production process of sugar nucleotides has not so far been established.
Examples of the known process for producing complex carbohydrates include 1) chemical synthetic processes (Method in Enzymol., 247, 193 (1994), Angew. Chem. Int. Ed. Engl., 21, 155 (1982), Carbohydr. Res., 211, cl (1991)), 2) processes in which a hydrolase is used (Anal. Biochem., 202, 215 (1992), Trends Biotechnol., 6, 256 (1988)) and 3) processes in which a glycosyltransferase is used (Japanese Published Unexamined Patent Application No. 79792/95, Japanese Published National Publication No. 500248/95, Japanese Published Examined Patent Application No. 82200/93, WO 94/25614, Japanese Published National Publication No. 503905/97, U.S. Pat. No. 5,583,042).
The introduction of protecting groups is essential for stereo-selective synthesis in the process 1). The yield and selectivity are not sufficient in the process 2). Expensive materials (for example, NDP, NTP, phosphoenolpyruvic acid, sugar phosphate, sugar nucleotide, etc.) and various enzymes (for example, pyruvate kinase, etc.) are necessary in the process 3). Therefore, these processes have not been established as inexpensive industrial production processes of complex carbohydrates. In addition, there has been nothing known about a process for the direct industrial production of complex carbohydrates, which uses only inexpensive nucleotide precursors, sugars and complex carbohydrate precursors as the starting materials.
It has been reported that UMP is produced in a microorganism belonging to the genus Corynebacterium when orotic acid is added (Amino Acid, Nucleic Acid, 23, 107 (1971)). In addition, a process in which cytidine diphosphate choline is formed from orotic acid as the material is also known (Japanese Published Unexamined Patent Application No. 276974/93).